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Unique Regulation of c-Jun N-Terminal Kinase by PYK2/CAK-β in Angiotensin II-Stimulated Vascular Smooth Muscle Cells

https://doi.org/10.1006/bbrc.2001.5463Get rights and content

Abstract

Activation of tyrosine kinases is believed to play a central role in angiotensin II (AngII) signaling. Here, we have investigated whether a tyrosine kinase, PYK2, is functionally involved in AngII-induced c-Jun N-terminal kinase (JNK) activation in vascular smooth muscle cells (VSMCs). Adenovirus expressing PYK2 kinase-inactive mutant K457A or a tyrosine phosphorylation site mutant Y402F was transfected in VSMCs. AngII-induced JNK phosphorylation was markedly enhanced by K457A, whereas it was suppressed by Y402F. Protein synthesis induced by AngII was also enhanced by K457A and inhibited by Y402F. In this regard, K457A suppressed PYK2 kinase activation by AngII, whereas it enhanced AngII-induced PYK2 Tyr402 phosphorylation. By contrast, Y402F inhibited PYK2 Tyr402 phosphorylation, whereas it markedly enhanced AngII-induced PYK2 kinase activation. Thus, we conclude that PYK2 kinase activity negatively regulates JNK activation and protein synthesis, whereas Tyr402 phosphorylation positively regulates these events in AngII-stimulated VSMCs, suggesting a unique role of PYK2 in mediating vascular remodeling.

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      We demonstrated recently that Pyk2H, an alternatively spliced isoform of Pyk2, is involved in JNK activation in T cells (17). We further found that the phosphorylation of Pyk2H tyrosine 402 is crucial for the JNK activation; this is also verified in a different system, i.e. angiotensin II signaling in smooth muscle cells (35). As shown in Fig.7, A and B, anti-Pyk2H immunoprecipitates from the lysates of JT-Pyk2H included a significant amount of Chat-H, and anti-Chat-H-precipitates from JT-Chat-H contained Pyk2H.

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